Apparatus and methods for delivering therapeutic agents

ABSTRACT

In various embodiments, a drug-delivery device includes one or more reservoirs that may each contain a therapeutic agent for delivery to a patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of, and incorporates hereinby reference in its entirety, U.S. patent application Ser. No.12/340,095, filed on Dec. 19, 2008, which claims priority to and thebenefit of, and incorporates herein by reference in their entireties,U.S. Provisional Patent Application No. 61/015,509, which was filed onDec. 20, 2007, and U.S. Provisional Patent Application No. 61/197,750,which was filed on Oct. 30, 2008.

TECHNICAL FIELD

In various embodiments, the invention relates to apparatus and methodsfor delivering therapeutic agents to a patient's body part, such as, forexample, to a patient's eye.

BACKGROUND

Medical treatment often requires the administration of a therapeuticagent (e.g., medicament, drugs, etc.) to a particular part of apatient's body. Intravenous injection has long been a mainstay inmedical practice to deliver drugs systemically. Some maladies, however,require administration of drugs to anatomical regions to which access ismore difficult to achieve.

A patient's eye is a prime example of a difficult-to-reach anatomicalregion. Ocular pathologies, such as diabetic retinopathy and maculardegeneration, are typically treated by administration of drugs to thevitreous humor, which has no fluid communication with the vasculature.Such administration not only delivers the drug directly to where it isneeded, but also minimizes the exposure of the rest of the patient'sbody to the drug and, therefore, to its potential side effects.

Injection of drug into the patient's body (e.g., into the vitreous humorof the eye), while medically feasible, typically delivers a bolus of thedrug. Bolus injections may, however, present several problems. First,their use in treating chronic eye conditions typically necessitatesrepeated injections into the eye, a painful procedure that generallyrequires repeated and expensive visits to a physician's office, and cancause trauma to the eye. Second, because a bolus injection intrinsicallyproduces a sawtooth-profile dependence of drug concentration over time,the dosage of the injection tends to be near the threshold limit oftoxicity. Injection of such dosages typically increases the likelihoodof systemic side effects, as occurs, for example, with ranibizumab.

A need therefore exists for apparatus and methods of administeringappropriately chosen therapeutic drugs to the eye so that the timevariation of the concentrations of those drugs in the eye is minimized.

SUMMARY OF THE INVENTION

In various embodiments, the present invention features apparatus andmethods for delivering therapeutic agents to a patient's body part, suchas, for example, to a patient's eye. In one approach, a drug-deliverydevice features a single reservoir for delivering one of a variety oftherapeutic agents to the patient. In another approach, thedrug-delivery device features multiple reservoirs for delivering morethan one different therapeutic agent to the patient, for example in astaged or alternating fashion.

Accordingly, in one aspect, embodiments of the invention feature adrug-delivery device that includes a first reservoir for containing afirst liquid having a first therapeutic agent, a second reservoir forcontaining a second liquid having a second therapeutic agent differentfrom the first therapeutic agent, and at least one cannula in fluidcommunication with the first and second reservoirs (e.g., a firstcannula in fluid communication with the first reservoir and a second,separate cannula in fluid communication with the second reservoir). Theat least one cannula may have an outlet for separately delivering thefirst and second liquids to the patient. In various embodiments, thefirst reservoir in fact includes the first liquid and the secondreservoir includes the second liquid.

In general, in another aspect, embodiments of the invention feature amethod for treating an ophthalmic condition. The method includesproviding a drug-delivery device as just described, attaching thedrug-delivery device onto the conjunctiva of a patient's eye such thatthe outlet of the at least one cannula penetrates the conjunctiva,filling the first reservoir with the first liquid having the firsttherapeutic agent, filling the second reservoir with the second liquidhaving the second therapeutic agent (which is different from the firsttherapeutic agent), and separately delivering the first and secondtherapeutic agents to the patient via the outlet of the at least onecannula.

In various embodiments, each of the first and second therapeutic agentstreats glaucoma and/or ocular hypertension. In such a case, the firstand second therapeutic agents may each be selected from the groupconsisting of acetazolamide, betaxolol, bimatoprost, brimonidine,brinzolamide, carbidopa, carteolol, dorzolamide, epinephrine,latanoprost, levodopa, levobunolol, levobetaxolol, loratadine,metipranolol, pilocarpine, pseudoephedrine, timolol, travoprost, andunoprostone isopropyl. In another embodiment, the first and secondtherapeutic agents treat age-related macular degeneration, macular edemaassociated with diabetic retinopathy, and/or macular edema associatedwith retinovascular occlusive diseases. In this case, the first andsecond therapeutic agents may be selected from the group consisting ofranibizumab, pegaptanib, verteporfin, bevacizumab, a steroid, a drugthat prevents beta amyloid deposition in the retina, an anti-humancomplement activation blocker that blocks complement H activation in theeye, and small interfering RNA (siRNA) molecules. In yet anotherembodiment, each of the first and second therapeutic agents treatcytomegalovirus retinitis and may be selected from the group consistingof valganciclovir, vitravene, and cidofovir. In still anotherembodiment, each of the first and second therapeutic agents treatitching and allergic conjunctivitis and may be selected from the groupconsisting of loteprednol etabonate, naphazoline, pheniramine maleate,pemirolast, and ketotifen fumarate.

In an alternative embodiment, the first and second therapeutic agentsare chosen so as to treat two different maladies selected from the groupconsisting of glaucoma, ocular hypertension, age-related maculardegeneration, macular edema associated with diabetic retinopathy,macular edema associated with retinovascular occlusive diseases, lowtear production, cytomegalovirus retinitis, bacterial conjunctivitis,itching and allergic conjunctivitis, post-operative eye inflammation,inflammation of the cornea due to herpes simplex virus, postoperativeinflammation after cataract extraction, corneal ulcers, and Sjögren'ssyndrome.

In another embodiment of the drug-delivery device, each of the first andsecond therapeutic agents treats recurrent malignant glioma and/ormalignant brain tumors. In such a case, the first and second therapeuticagents may each be selected from the group consisting of bevacizumab,irinotecan, and a steroid. In yet another embodiment, each of the firstand second therapeutic agents suppresses an inflammatory reaction. Inthis case, the first therapeutic agent may be a steroid and the secondtherapeutic agent may be either a non-steroidal drug or an anti-cancerdrug. In still another embodiment, each of the first and secondtherapeutic agents provides neuroprotection for a retinal disease,glaucoma, and/or a brain disorder. For example, each of the first andsecond therapeutic agents is selected from the group consisting of abrain derived growth factor, a ciliary neurotrophic factor, a basicfibroblast growth factor, a nerve growth factor, and a tumor necrosisgrowth factor inhibitor.

In an alternative embodiment, the first and second therapeutic agentsare chosen so as to treat two different maladies selected from the groupconsisting of recurrent malignant glioma, a malignant brain tumor,alzheimers, cerebral edema, and an inflammatory reaction.

In general, in yet another aspect, embodiments of the invention featurea drug-delivery device that includes a reservoir and a cannula in fluidcommunication with the reservoir. The reservoir contains a liquid thatincludes a therapeutic agent, and the cannula has an outlet fordelivering the therapeutic agent to a patient.

In general, in still another aspect, embodiments of the inventionfeature a method for treating an ophthalmic condition. The methodincludes implanting a drug-delivery device in a patient's eye andfilling the drug-delivery device with a liquid that includes atherapeutic agent.

In various embodiments of each of these latter two aspects, thetherapeutic agent is selected from the group consisting ofacetazolamide, betaxolol, bevacizumab, bimatoprost, brimonidine,brinzolamide, carbidopa, carteolol, cidofovir, cyclosporine,dorzolamide, epinephrine, a growth factor, irinotecan, ketorolactromethamine, ketotifen fumarate, latanoprost, levobetaxolol,levobunolol, levodopa, levofloxacin, loratadine, loteprednol etabonate,metipranolol, naphazoline, ofloxacin, pegaptanib, pemirolast,pheniramine maleate, pilocarpine, pseudoephedrine, ranibizumab, asteroid, timolol, travoprost, trifluridine, tumor necrosis factorblocker, unoprostone isopropyl, valganciclovir, verteporfin, vitravene,a drug that prevents beta amyloid deposition in the retina or in thebrain, an anti-human complement activation blocker that blockscomplement H activation in the eye, and siRNA molecules.

In general, in a further aspect, embodiments of the invention feature amethod for treating a cancerous condition. The method includesimplanting a drug-delivery device near a patient's tumor and filling thedrug-delivery device with a combination of drugs. The combination ofdrugs may be, for example, one of the following: i) bevacizumab andCPT-11; ii) ranibizumab and CPT-11; iii) letrozole and tamoxifen; iv)doxorubicin and docetaxel; v) bevacizumab and any chemotherapy drug; vi)gemcitabine and CP-870,893; vii) PF-3512676 and a cytotoxic chemotherapydrug; viii) bevacizumab and paclitaxel; ix) docetaxel and sunitinib; x)bevacizumab and sunitinib; xi) lapatinib and letrozole; xii) ixabepiloneand capecitabine; and xiii) paclitaxel protein-bound and a taxane.

In general, in an additional aspect, embodiments of the inventionfeature a drug-delivery device that includes a first reservoir forcontaining a first liquid having a first therapeutic agent, a secondreservoir for containing a second liquid having a second therapeuticagent different from the first therapeutic agent, memory for storing adrug-delivery regimen, and a microprocessor for controlling a deliveryof the first and second liquids to a patient through at least onecannula based on an execution of the stored drug-delivery regimen.

In various embodiments, the drug-delivery device also includes a sensorfor receiving feedback from the patient and/or a receiver for receivingwireless instructions (e.g., from a physician) that reprogram thedrug-delivery regimen. The microprocessor may also modify thedrug-delivery regimen based on the feedback. The feedback may be, forexample, a measured eye pressure for the patient, a position of thepatient, an activity being undertaken by the patient, and/or a measuredresidual amount of the first or second therapeutic agent present in apatient's tissue. In addition, execution of the drug-delivery regimenmay be impacted by a variable such as the time of day, apatient-specific factor, and/or identities of the first and secondtherapeutic agents.

These and other objects, along with advantages and features of theembodiments of the present invention herein disclosed, will become moreapparent through reference to the following description, theaccompanying drawings, and the claims. Furthermore, it is to beunderstood that the features of the various embodiments described hereinare not mutually exclusive and can exist in various combinations andpermutations.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, like reference characters generally refer to the sameparts throughout the different views. Also, the drawings are notnecessarily to scale, emphasis instead generally being placed uponillustrating the principles of the invention. In the followingdescription, various embodiments of the present invention are describedwith reference to the following drawings, in which:

FIG. 1A is an exploded view of a drug-delivery device in accordance withone embodiment of the invention;

FIG. 1B is an assembled view of the exemplary drug-delivery devicedepicted in FIG. 1A;

FIG. 2 illustrates a drug-delivery device implanted in a patient's eyein accordance with one embodiment of the invention;

FIG. 3 is a cross-sectional view of a portion of the exemplarydrug-delivery device depicted in FIG. 1B;

FIGS. 4A and 4B are cross-sectional views illustrating the operation ofa valve for a drug-delivery device in accordance with one embodiment ofthe invention;

FIG. 5A is a top view of another drug-delivery device in accordance withone embodiment of the invention;

FIG. 5B is a top view of yet another drug-delivery device in accordancewith one embodiment of the invention;

FIG. 6 illustrates a drug-delivery device that utilizes electrolyticpumping in accordance with one embodiment of the invention;

FIGS. 7A and 7B illustrate a top-cross-sectional view and aside-cross-sectional view, respectively, of an electrolysis micropump inaccordance with one embodiment of the invention;

FIGS. 8A and 8B illustrate top and cut-away side views, respectively, ofan electrolysis micropump in accordance with one embodiment of theinvention;

FIGS. 9A-9D illustrate successive cut-away views of a drug reservoir andpump chamber in accordance with one embodiment of the invention;

FIG. 10 illustrates one embodiment of a drug-delivery system with drugreservoir, cannula, valving, pump, refillable port, and suture tabs;

FIG. 11 illustrates the internal structure of one type of injection porton the reservoir in accordance with one embodiment of the invention;

FIGS. 12A-12K illustrate a process flow for fabricating a silicon maskand making a molded polydimethylsiloxane (PDMS) layer in accordance withone embodiment of the invention;

FIGS. 13A-13M illustrate a process flow for fabricating the base layerof an implantable drug-delivery device that includes electrodes forelectrolytic pumping and an integral cannula in accordance with oneembodiment of the invention;

FIG. 14 illustrates (a) flow-rate testing results for an exemplaryelectrolysis pump; (b) ultra-low flow rate testing results for theexemplary electrolysis pump; (c) the pump efficiency as calculated fromthe flow delivery data; and (d) the typical gas recombination observedin the pump;

FIG. 15 illustrates bolus delivery of 250 nL doses using current pulsesin an exemplary electrolysis pump; and

FIG. 16 illustrates the flow performance of an exemplary electrolysispump under typical physiological back pressures.

DESCRIPTION

In general, embodiments of the present invention pertain to apparatusand methods for delivering therapeutic agents to a patient's body part,such as, for example, to the patient's eye. In certain embodiments, theimplantable drug-delivery device for the eye combines small size and arefillable reservoir. The small size minimizes discomfort from thedevice to the patient's eye, while the refillable reservoir allows thedevice to be refilled in situ, rather than being replaced. As such, afluid, such as a solution of a drug, can be supplied to the patient'seye over extended periods of time.

In certain embodiments, the drug-delivery device includes the refillablereservoir, a cannula, and a valve. The refillable reservoir holds thefluid to be delivered, the cannula directs the fluid to the targetedsite, and the valve controls the delivery of the fluid and preventsbackflow. In one embodiment, the refillable reservoir has aself-resealing upper layer that can be pierced with a needle forrefilling, and a lower layer that resists needle punctures and therebyprotects the eye from accidental injury during the refilling process.For its part, the cannula may be tapered to facilitate its insertioninto the patient's eye.

FIGS. 1A and 1B schematically illustrate an exploded view and anassembled view, respectively, of one embodiment of a drug-deliverydevice 5. The device 5 includes a reservoir 100 that is configured tocontain a liquid comprising a therapeutic agent (e.g., a drug), and acannula 110 that is in fluid communication with the reservoir 100. At ornear its distal end 117, the cannula 110, which is configured forinsertion into a patient (e.g., into a patient's eye), includes anoutlet 115 for delivering the drug to the patient. In addition, asdescribed further below, the drug-delivery device 5 may also include avalve 120 positioned at or near the distal end 117 of the cannula 110.Alternatively, the valve 120 may be positioned elsewhere along thelength of the cannula 110, such as at its end proximal the reservoir100.

In one embodiment, the reservoir 100 is a refillable multi-layeredstructure having a first wall 10 that is puncturable by a needle and asecond, opposite wall 50 that is generally unpuncturable by the needle.As explained further below, the needle is used in refilling thereservoir 100 with a liquid comprising a therapeutic agent, such as adrug. The first wall 10 may include a pliable, drug-impermeable polymer(e.g., silicone) layer that does not leak after being pierced by aneedle, while the second wall 50 may include a layer having a lesspliable and more mechanically robust material (e.g., a stiffer material,such as a polymer or a composite). Alternatively, the second wall 50 mayinclude a greater thickness of the same material used to fabricate thefirst wall 10. In certain embodiments in which the drug-delivery device5 is implanted in or on a patient's eye, the second wall 50 is placedadjacent to the sclera of the eye, and the greater mechanical strengthof the second wall 50 limits the stroke of the needle used to puncturethe first wall 10 to refill the reservoir 100. In this fashion, the eyeis protected from accidental punctures. The reservoir 100 may be formedby bonding the first wall 10 and the second wall 50 either to each otheror to one or more intervening layers 20, as described more fully below.

In one embodiment, the reservoir 100 includes integral mechanicalsupport structures 60 that reduce the possible contact area between thefirst wall 10 and the second wall 50 and that prevent the reservoir 100from collapsing completely. The mechanical support structures 60 may be,or include, one or more protrusions (e.g., posts) extending from atleast one of the first wall 10 and the second wall 50. Other mechanicalsupport structures are also compatible with various embodimentsdescribed herein.

In one embodiment, the cannula 110 includes an elongate first portion 70and a wall 30 that together define a lumen 72 through the cannula 110.The cannula 110 may also include one or more integral mechanical supportstructures 74 in the lumen 72 to prevent the cannula 110 from collapsingand occluding the lumen 72. For example, the mechanical supportstructures 74 may be, or include, one or more protrusions (e.g., posts)extending from an inner surface of the first portion 70 of the cannula110 towards the wall 30 of the cannula 110. In certain embodiments, themechanical support structures 74 have a height that extends from theinner surface of the first portion 70 to the wall 30 and a width thatextends less than the full width of the lumen 72. Other mechanicalsupport structures are also compatible with various embodimentsdescribed herein.

The end 117 of the cannula 110 may be configured to be inserted into apatient's eye. For example, the end 117 of the cannula 110 may betapered to facilitate insertion into the eye. In certain otherembodiments, the end 117 has rounded corners that facilitate insertioninto the eye. In one embodiment, the outer diameter of the cannula 110is less than or equal to the outer diameter of a 25-gauge needle. Inanother embodiment, the outer diameter of the cannula 110 is less than 1millimeter (e.g., 0.5 millimeters). In embodiments in which thedrug-delivery device 5 is implantable in, or on, the eye, the outerdiameter of the cannula 110 is sufficiently small to obviate the needfor sutures at the insertion site to help maintain the integrity of theeye.

The cannula 110 may also include one or more flow-regulator structures(e.g., valves) to maintain a constant flow rate. In this way, theadministered dosage of a drug depends on the duration that fluidcontaining the drug flows through the cannula 110, rather than on themagnitude of an applied pressure that drives fluid flow through thecannula 110. More accurate control of the administered dosage maythereby be obtained, and the dosage remains independent of externalmechanical influence (e.g., if the patient rubs his or her eye). Insteadof, or in addition to, the one or more flow-regulator structures of thecannula 110, the reservoir 100 may include one or more suchflow-regulator structures.

In addition, the cannula 110 may include one or more fluid-flowisolation structures (e.g., valves) that isolate the reservoir 100 froma patient's body (e.g., the eye) during various operations that involvethe reservoir 100 (e.g., purging, cleaning, and/or refilling), therebypreventing the exchange of fluid (in either direction) between thereservoir 100 and the patient's body. Instead of, or in addition to, theone or more fluid-flow isolation structures of the cannula 110, thereservoir 100 may include one or more such fluid-flow isolationstructures.

FIG. 2 schematically illustrates the exemplary drug-delivery device 5implanted in the eye of a patient in accordance with one embodiment ofthe invention. As illustrated, the device 5 is placed upon theconjunctiva of the eye, and cannula 110 is inserted therethrough in tothe posterior chamber of the eye. As described more fully below, incertain embodiments, the reservoir 100 includes a needle-pierceableportion in the first wall 10 that serves as a fill port for thereservoir 100. The drug-delivery device 5 administers fluid to theposterior chamber of the eye through the cannula 110 and the valve 120.In other embodiments, the device 5 is used to administer fluid to theanterior chamber of the eye, which is separated from the posteriorchamber by the lens.

The device 5 may also be implanted in other portions of the body. Forexample, the device 5 may be implanted in the sub-arachnoid space of thebrain to provide chemotherapy or to provide another type of treatmentfor the brain as described below, near a tumor in any portion of thepatient's body to provide chemotherapy, or in a pancreas that does notrespond well to glucose to provide agents (e.g., proteins, viralvectors, etc.) that will trigger insulin release.

As mentioned, in one embodiment, the drug-delivery device 5 isrefillable. With reference again to FIG. 1A, the first wall 10 of thereservoir 100 may be puncturable by a needle (not shown), therebyallowing the reservoir 100 to be refilled through the needle. In oneembodiment, at least a portion of the first wall 10 is self-sealing. Forexample, a self-sealing portion may include a soft plastic material thatcan be punctured with the needle and that reseals itself upon removal ofthe needle. In one embodiment, the self-sealing material advantageouslyprovides a reservoir refill site that can withstand multiple punctures,and is biocompatible. Examples of materials that may be employed for theself-sealing material include, but are not limited to, PDMS, parylene C,parylene HT, polycarbonates, polyolefins, polyurethanes, copolymers ofacrylonitrile, copolymers of polyvinyl chloride, polyamides,polysulphones, polystyrenes, polyvinyl fluorides, polyvinyl alcohols,polyvinyl esters, polyvinyl butyrate, polyvinyl acetate, polyvinylidenechlorides, polyvinylidene fluorides, polyimides, polyisoprene,polyisobutylene, polybutadiene, polyethylene, polyethers,polytetrafluoroethylene, polychloroethers, polymethylmethacrylate,polybutylmethacrylate, polyvinyl acetate, nylons, cellulose, gelatin,silicone rubbers and porous rubbers. Where the self-sealing materialincludes a plastic that is capable of leaching or absorbing drugs thatcome into contact with it (e.g., silicone), parylene may be coated overthe plastic so that less drug is exposed to the plastic.

To illustrate the stability of PDMS as a material for the first wall 10,three different needle styles were inserted into a slab of PDMS: (i) a20-gauge standard sharp-tipped needle, (ii) a 30-gauge non-coringneedle, and (iii) a 30-gauge coring needle. The puncture sites were thenobserved using scanning electron microscopy and optical microscopy. The20-gauge standard sharp-tipped needle and the 30-gauge non-coring needleallowed the PDMS to self-seal the puncture hole after the needle wasremoved. However, the 30-gauge coring needle left a channel in the PDMSafter it was removed. The puncture mechanism in small-diameter needlesof either standard or non-coring styles appears to tear and displace thePDMS material rather than removing material, thereby allowing the PDMSto reseal the puncture hole. In addition, the structural integrity ofthe PDMS was observed after multiple punctures with a 25-gauge needle.Table 1 shows the relationship between the thickness of the wall 70 andleakage for tests performed under atmospheric conditions with leakagedetermined through visual inspection.

TABLE 1 Wall Thickness Number of Punctures (millimeters) Until Failure0.3557 1 0.5080 7 0.4826 10 0.4578 22 0.5334 21

The refillable reservoir 100 may be used with a variety ofdrug-containing fluids, depending upon the type of malady being treated.Typically, the pharmaceuticals chosen for eye treatment will penetratethe protective physiological barriers of the eye such as the cornea,sclera, and the blood-retina barrier. In addition, the pharmaceuticalswill target difficult-to-reach intraocular tissues such as the ciliarybody, retina, and angle. As examples, fluids containing the followingtherapeutic agents, either alone or in proper combination, may be usedwith the drug-delivery devices described herein for the treatment of thefollowing maladies:

-   -   i) acetazolamide, betaxolol, bimatoprost, brimonidine,        brinzolamide, carbidopa, carteolol, dorzolamide, epinephrine,        latanoprost, levodopa, levobunolol, levobetaxolol, loratadine,        metipranolol, pilocarpine, pseudoephedrine, timolol, travoprost,        and unoprostone isopropyl for the treatment of glaucoma and/or        ocular hypertension;    -   ii) ranibizumab, pegaptanib, verteporfin, bevacizumab (e.g.,        Avastin®), steroids (such as fluocinolone and triamcinolone        (e.g., Kenalog®)), drugs that prevent beta amyloid deposition in        the retina (such as tarenflurbil (e.g., Flurizan®), anti-human        complement activation blockers to block complement H activation        in the eye, and siRNA molecules (the delivery of which may be        appropriately titrated) for the treatment of age-related macular        degeneration and/or the macular edema associated with diabetic        retinopathy and retinovascular occlusive diseases;    -   iii) cyclosporine ophthalmic emulsion for the treatment of low        tear production;    -   iv) valganciclovir, vitravene, and cidofovir for the treatment        of cytomegalovirus retinitis;    -   v) levofloxacin for the treatment of bacterial conjunctivitis;    -   vi) loteprednol etabonate, naphazoline, pheniramine maleate,        pemirolast, and ketotifen fumarate for the treatment of itching        and allergic conjunctivitis;    -   vii) loteprednol etabonate for the treatment of post-operative        eye inflammation;    -   viii) trifluridine for the treatment of inflammation of the        cornea in children due to herpes simplex virus;    -   ix) ketorolac tromethamine for the treatment of postoperative        inflammation after cataract extraction;    -   x) ofloxacin for the treatment of corneal ulcers;    -   xi) pilocarpine for the treatment of Sjögren's syndrome, an        autoimmune disorder;    -   xii) bevacizumab (e.g., Avastin®), irinotecan (also known as        CPT-11), and steroids for the treatment of adult patients having        recurrent malignant glioma and/or for the treatment of pediatric        patients having high risk malignant brain tumors;    -   xiii) drugs that prevent beta amyloid deposition in the brain        (such as tarenflurbil (e.g., Flurizan®) for the treatment of        alzheimers;    -   xiv) steroids to reduce edema following a central nervous system        stroke and/or to reduce cerebral edema following head trauma;    -   xv) steroids in combination with non-steroidal drugs, or        steroids in combination with anti-cancer drugs (e.g., tumor        necrosis factor blocker), to suppress inflammatory reactions        (e.g., macrophages); and    -   xvi) growth factors, such as brain derived growth factor,        ciliary neurotrophic factor, basic fibroblast growth factor, and        nerve growth factor, and tumor necrosis growth factor inhibitor        for neuroprotection in retinal diseases, glaucoma, and/or brain        disorders.

Because the refillable reservoir 100 can be used with a variety ofdifferent drug containing fluids, it may be, in some cases, desirable toremove any remaining fluid from the reservoir 100 before refilling.Remaining fluid in the reservoir 100 may be removed therefrom by, forexample, inserting a needle or syringe through the self-sealing portionof the first wall 10 to suck out the fluid from the reservoir 100. Then,the reservoir 100 may be refilled with a new drug-containing fluid viaanother needle or syringe inserted through the self-sealing portion ofthe first wall 10. Purging, if desired, can be effected through repeatedcycles of injection and removal of a purging fluid.

In one embodiment, the refillability of the reservoir 100 allows thedrug-delivery device 5 to be smaller than it may otherwise be becausethe reservoir 100 need not be sufficiently large to hold a lifetimesupply of the drug to be administered. The smaller size of thedrug-delivery device 5 advantageously reduces the invasiveness of thedevice 5 both for implantation and daily use.

In addition, the refillability of the reservoir 100 may advantageouslyallow a physician to tailor a therapeutic regimen to a patient'schanging needs or to take advantage of new advances in medicine. In oneembodiment, the refillable reservoir 100 stores at least a one-monthsupply of the drug (e.g., a six-month supply) to reduce the number ofrefills required.

FIG. 3 schematically illustrates a cross-sectional view of oneembodiment of the valve 120 at the distal end 117 of the cannula 110.The cross-sectional view of FIG. 3 is in the plane indicated by thedashed line of FIG. 1B. The valve 120 may include a valve seat 80 and anelement movable between first and second positions. FIGS. 4A and 4Bschematically illustrate cross-sectional views of the valve 120 with amovable element 122 in the first and second positions, respectively. Inone embodiment, a flexible portion of the wall 30 of the cannula 110forms the movable element 122, and the movable element 122 features anorifice 40 therethrough. The movable element 122 is movable between thefirst position (as schematically illustrated by FIG. 4A) in which theportion of the wall 30 does not contact the valve seat 80, and thesecond position (as schematically illustrated by FIG. 4B) in which theportion of the wall 30 contacts the valve seat 80 such that the orifice40 is occluded. Liquid may flow through the orifice 40 to the outlet 115of the cannula 110 when the movable element 122 is in the firstposition. However, the liquid is prevented from flowing through theorifice 40 to the outlet 115 when the movable element 122 is in thesecond position. As such, the valve 120 may prevent both unwanteddiffusion of drug from the drug-delivery device 5 into the target organand unwanted backflow of material from the patient's body into thecannula 110.

In one embodiment, the valve seat 80 is a protrusion (e.g., post) thatextends from an inner surface of the cannula 110 towards the movableelement 122 (e.g., the flexible portion of the wall 30), as shownschematically in FIGS. 4A and 4B. The protrusion may be substantiallyidentical to the one or more integral mechanical support structures 74in the lumen 72 of the cannula 110 described above.

In certain embodiments, the movable element 122 moves from the secondposition (FIG. 4B) to the first position (FIG. 4A) in response topressure applied to the portion of the wall 30 by fluid within thecannula 110. For example, mechanical (e.g., manual) pressure applied toone or more walls 10, 50 of the reservoir 100 can force fluid throughthe cannula 110 such that the fluid pressure opens the valve 120. Incertain embodiments, the valve 120 opens only when the fluid pressureinside the cannula 110 exceeds a predetermined threshold value greaterthan the fluid pressure outside the cannula 110. The valve 120 remainsclosed when the fluid pressure inside the cannula 110 is equal to orless than the fluid pressure outside the cannula 110, thereby preventingbiological fluids from flowing backwards into the drug-delivery device5.

FIG. 5A schematically illustrates a top view of another embodiment of adrug-delivery device 90. As illustrated, rather than featuring a singlereservoir 100 having a single cannula 110 in fluid communicationtherewith, the drug-delivery device 90 includes two reservoirs 100A,100B. Each reservoir 100A, 100B has a single, different cannula 110A,110B in fluid communication therewith. In one embodiment, each reservoir100A, 100B contains a different therapeutic agent in liquid form. Thisallows for the separate administration of two different drugs, forexample in a staged or alternating fashion.

Each reservoir/cannula pair of the drug-delivery device 90 may be aseparate pump that features one or all of the elements described abovewith reference to the embodiments of the drug-delivery device 5 depictedin FIGS. 1A through 4B, and that operates in an analogous fashion. Forexample, mechanical (e.g., manual) pressure applied to one or more wallsof the reservoir 100A can force a first therapeutic fluid through thecannula 110A such that the first fluid exits the outlet 115A. Then,mechanical (e.g., manual) pressure applied to one or more walls of thereservoir 100B can force a second, different therapeutic fluid throughthe cannula 110B such that the second fluid exits the outlet 115B.Alternatively, each reservoir/cannula pair of the drug-delivery device90 may in fact be implemented as a separate electrolytic pump, asdescribed below with reference to the embodiments of the drug-deliverydevice 200 depicted in FIGS. 6 through 10, and be individuallycontrolled in order to deliver to the patient an optimal therapeuticdosage of each of the different drugs.

While the drug-delivery device 90 is illustrated as having only tworeservoir/cannula pairs, it may in fact be manufactured to have three,four, or any number of reservoir/cannula pairs. In addition, rather thanhaving a single, separate cannula in fluid communication with eachreservoir (as illustrated in FIG. 5A), a single cannula 110 may in factbe in fluid communication with two, three, four, or more reservoirs, asillustrated in FIG. 5B. In such a case, additional valves 112 mayoptionally be employed, as illustrated, in the different portions of thecannula 110 that branch off to each reservoir in order to preventfluidic communication between the reservoirs.

In one embodiment, where the drug-delivery device 90 includes tworeservoirs 100A, 100B, the volume of each reservoir ranges from, forexample, 63 μL to 105 μL. For example, each reservoir 100A, 100B mayhave a width w of approximately 3 mm, a depth d of approximately 7 mm,and a height ranging from 3 mm to 5 mm. In such an embodiment, theoverall dimensions of the drug-delivery device 90 may be within an 8mm×8 mm footprint with a height of 3 mm to 5 mm. Processes formanufacturing the drug-delivery device 90 may be as described below withreference to FIGS. 12A-12K and 13A-13M for the single reservoirdrug-delivery devices 5 and 200, respectively.

By utilizing two or more reservoirs, different combinations and/orsequences of different drugs may be appropriately employed to treatdifferent maladies. For example, a drug-delivery device 90 featuringtwo, three, four, or more reservoirs may be employed to deliverappropriate amounts of ranibizumab, pegaptanib, verteporfin,bevacizumab, and/or a steroid, such as fluocinolone or triamcinolone, totreat age-related macular degeneration and/or the macular edemaassociated with diabetic retinopathy and retinovascular occlusivediseases. In addition, one or more reservoirs in such a device 90 may beemployed to deliver, in combination with one or more of those drugs,drugs that prevent beta amyloid deposition in the retina (such astarenflurbil), anti-human complement blockers to block complement Hactivation in the eye, and siRNA molecules. In another embodiment, twodifferent isoforms of an anti vascular endothelial growth factor(anti-VEGF) are employed to treat the age-related macular degeneration.In many cases, age-related macular degeneration is caused bypolymorphisms on chromosomes 1 and 10. Accordingly, embodiments of theinvention may be employed to customize the dosage of different amountsof anti-VEGF variants in order to customize treatment for a patientbased on his or her genetic make-up.

As another example, a drug-delivery device 90 featuring three reservoirsmay be employed to deliver appropriate amounts of valganciclovir,vitravene, and cidofovir to treat cytomegalovirus retinitis, or adrug-delivery device 90 featuring two reservoirs may be employed todeliver appropriate amounts of two of those drugs to treat thecytomegalovirus retinitis. Similarly, a drug-delivery device 90featuring two, three, or more reservoirs may be employed to deliverappropriate amounts of any of the drugs identified above for thetreatment of glaucoma and/or ocular hypertension, or, alternatively, todeliver appropriate amounts of any of the drugs identified above for thetreatment of itching and allergic conjunctivitis, in any combinationdeemed suitable by a physician. In addition, a drug-delivery device 90featuring two, three, or more reservoirs may be employed to deliver, inany combination deemed suitable by a physician: i) different drugs forpreventing beta amyloid deposition in the brain during the treatment ofalzheimers; ii) different steroids for reducing edema following acentral nervous system stroke; iii) different steroids for reducingcerebral edema following head trauma; iv) steroids in combination withnon-steroidal drugs to suppress inflammatory reactions (e.g.,macrophages); v) steroids in combination with anti-cancer drugs (e.g.,tumor necrosis factor blocker) to suppress inflammatory reactions (e.g.,macrophages); or vi) appropriate amounts of any of the growth factorsidentified above and/or tumor necrosis growth factor inhibitor forneuroprotection in retinal diseases, glaucoma, and/or brain disorders.In addition still, two or more different maladies (for example of any ofthe types described above) may be treated in parallel by a drug-deliverydevice 90 featuring two, three, or more reservoirs containing differentdrugs targeted towards treating those different maladies.

In chemotherapy, the delivery of multiple drugs can be very helpful infighting brain tumors. For example, combinations of bevacizumab (e.g.,Avastin®) and CPT-11 can be extremely effective in adult patientssuffering from recurrent malignant glioma or in pediatric patientshaving high risk malignant brain tumors. More specifically, Avastin® andCPT-11 combination therapy has demonstrated rapid clinical andradiographic improvement in patients with relapsed malignant glioma.Some patients have even achieved long term improvement. In addition, MRIscans of recurrent glioma patients treated with Avastin® and CPT-11 (aswell as with carboplatin and etoposide) have shown rapidcontrast-enhancing tumor shrinkage. In one embodiment, thedelivery-device 90 may be employed to pulse boluses of each drug to thebrain tumor at different intervals (e.g., Avastin® on odd days andCPT-11 on even days). Since Avastin® and CPT-11 work in differentfashions (i.e., Avastin® slows down blood vessel growth by inhibitingvascular endothelial growth factor (VEGF), a protein that plays a majorrole in angiogenesis and in the maintenance of existing blood vesselsthroughout the life cycle of a tumor, while CPT-11 disrupts nuclear DNAby inhibiting topoisomerase I, an enzyme that relaxes supercoiled DNAduring replication and transcription), pulsing boluses of each drug atdifferent intervals allows the drugs to work without interfering witheach other. In addition, steroids may be pulsed intermittently with theAvastin® or CPT-11 to aid the surrounding brain edema during tumortreatment.

As additional examples, specific combinations of the following drugs(e.g., in fluidic form), may be used with the drug-delivery device 90for the treatment of cancer: i) ranibizumab and CPT-11; ii) letrozoleand tamoxifen; iii) doxorubicin and docetaxel; iv) bevacizumab and anychemotherapy drug; v) gemcitabine and CP-870,893 (a CD40 agonistmonoclonal antibody); vi) PF-3512676 and a cytotoxic chemotherapy drug;vii) bevacizumab and paclitaxel; viii) docetaxel and sunitinib; ix)bevacizumab and sunitinib; x) lapatinib and letrozole; xi) ixabepiloneand capecitabine; and xii) paclitaxel protein-bound and other taxanes.

In one embodiment, in order to control (e.g., stagger or alternate) thedelivery of drugs from the multiple reservoirs 100, the drug-deliverydevice 90 further includes microelectronics, such as a microcontrolleror microprocessor 130, memory 132, a sensor 134, and a transceiver 136.More specifically, the memory 132 may store a drug-delivery regimen andthe microprocessor 130 may control the delivery of the drugs from thereservoirs 100 to the patient through the one or more cannulas 110 byexecuting the stored drug-delivery regimen. During execution of thestored drug-delivery regimen, the microprocessor 130 may issueinstructions to actuate mechanically, or through electrolysis (asdescribed below), a reservoir/cannula pair (i.e., pump) to release drugtherefrom. The stored drug-delivery regimen may be programmed tocontrol, for example, the amount, frequency, and type of drug releasedbased upon any applicable factor or variable. For example, the amount,frequency, and type of drug released may depend upon the time of day(e.g., larger amounts of a particular type of drug may be released morefrequently at night when the patient is sleeping), or uponpatient-specific factors, such as the severity of the patient's malady,the patient's tolerance for particular types of drugs, the patient'sbody weight, the patient's genetic make-up (which may be ascertainedfrom, for example, a genetic screening of the patient), etc. In oneembodiment, the stored drug-delivery regimen also includes programmablevariables identifying the types of drugs contained in the reservoirs110.

In one embodiment, the sensor 134 gathers feedback from the patient. Themicroprocessor 130 may then employ the feedback to modify thedrug-delivery regimen stored in the memory 132. For example, the sensor134 may measure the patient's eye pressure and the microprocessor 130may thereafter increase or decrease the amount and/or frequency at whichone or more of the multiple drugs being used in combination is released.As another example, the sensor 134 may determine the residual amount ofa first drug that is left in the patient's tissue and then, whenresidues of the first drug have disappeared, the microprocessor 130 mayissue instructions to cause a second drug may be delivered to thepatient. In one embodiment, the sensor 134 determines the residualpresence of the first drug in the patient's tissue by monitoring thephysiological effects of that first drug on the patient. For example,the sensor 134 may measure the patient's reaction to the first drug bysampling and analyzing the patient's blood.

In yet another embodiment, the sensor 134 determines the patient'sposition (e.g., if the patient's is lying horizontal or standingupright), for example through the use of a device such as a gyroscope.Moreover, the sensor 134 may be employed to monitor the patient's heartrate to determine the patient's activity (e.g., whether the patient isexercising or resting). The microprocessor 130 may then employ suchsensed information to deliver a drug, or combinations of drugs, to thepatient at an optimal time. For example, upon determining that thepatient is lying horizontal and is resting, and that the time of day is3:00 am, the microprocessor 130 may cause delivery of a drug to thepatient that is best administered when one is sleeping. As anotherexample, when the patient's sensed heart rate indicates that he or sheis exercising, a drug requiring adequate mixing may delivered to thepatient.

The functions described above may be implemented entirely within thedrug-delivery device 90 or, alternatively, the microelectronics may alsoinclude a transceiver 136 so that, in addition to certain functionsbeing implemented locally, functions may also be implemented remotely.In one embodiment, the transceiver 136 enables wireless communicationbetween the local and remote portions. Moreover, the transceiver 136 maybe employed to permit a physician to wirelessly reprogram thedrug-delivery regimen.

In general, the microprocessor 130 may be any logic circuitry thatresponds to and processes instructions fetched from the memory 132. Forexample, the microprocessor 130 may be one of the many general-purposemicroprocessor units manufactured by Intel Corporation of Mountain View,Calif. For its part, the memory 132 may be provided by one or morememory chips capable of storing data and allowing any storage locationto be directly accessed by the microprocessor 130. The drug-deliveryregimen stored in the memory 132 may programmed using any suitableprogramming language or languages (e.g., C++, C#, java, Visual Basic,LISP, BASIC, PERL, etc.). The transceiver 136 may be any hardwaredevice, or software module with a hardware interface, that is capable ofreceiving and transmitting communications, including requests,responses, and commands, such as, for example, inter-processorcommunications and wireless communications.

The ability to customize therapy by prescribing two or more varyingdosages in real-time (e.g., a doctor may wirelessly adjust dosages ifneeded) also minimizes uncomfortable and dangerous side effects for thepatient. One powerful combination for the eye is the ability, using thedelivery-device 90, to deliver combination therapy at different times ofthe day. For example, companies offer timolol and prostaglandincombination therapy (given topically in the same eye drop or in separateeye drops during different times of the day), but those drugs are nottypically injected directly in to the eye because of inconvenience anddiscomfort to the patient. Timolol has a peak action in the eyeapproximately one hour after the drops are administered, whileprostaglandins in the eye has a peak effect approximately four hoursafter topical administration. Therefore, in accordance with embodimentsdescribed herein, the drug-delivery device 90 may stagger drug deliveryto match the approved dosing peak effects of combination therapies fordiseases such as open-angle glaucoma.

In the prior art, for example, a patient may self administer at 7 pm anFDA approved single eye drop that contains timolol and prostagladins fora peak action of each drug at approximately 8 pm and 11 pm,respectively. In contrast, the drug-delivery device 90 may be programmedto pump each respective drug at different staggered times to reach thesame clinically desired effect when applied topically. Because drugstypically have different times of transport across the cornea whenadministered topically, but are not presented with that challenge wheninjected directly into the eye using the drug-delivery device 90, thedrug-delivery device 90 may be employed to match optimal clinicaleffects with staggered intracameral injections.

Exemplary fixed combinations of drugs that may be administered to thepatient using the drug-delivery device 90 include timolol0.5%/dorzolamide 2.0%, timolol 0.5%/brimonidine 0.2%, and fixedcombinations of prostaglandins plus timolol 0.5%, such as: timolol0.5%/latanoprost 0.005%, timolol 0.5%/travoprost 0.005%, and timolol0.5%/bimatoprost 0.03%.

Fixed combinations of drugs injected intracamerally with thedrug-delivery device 90 help to avoid medication washout, which mayoccur when a patient on multiple single drugs instills his or hervarious medications with too short an interval between eye drops. Infact, with multiple eye drops for multiple drugs, a significant washouteffect may occur when one drug causes another drug to be ineffective byincreasing outflow before a therapeutic effect has occurred. Moreover,although large clinical trials have shown the fixed combination oftimolol/dorzolamide to be equivalent to the unfixed combination (at mosttime points), real-world studies have demonstrated improved intraocularpressure (IOP) lowering for the fixed combination versus the unfixedcombination.

Current limitations with topical combination therapies include theinability to tailor individualized therapy as flexibly as with thecomponent drugs that can be administered using the drug-delivery device90. The rigidity of topical fixed combination therapy may prevent theoptimal dosing frequency or timing of some components (for example,having to use a beta-blocker twice daily when once daily may besufficient). In various embodiments, the pumps of the drug-deliverydevice 90 allow for different combination therapies during the day(e.g., drug A and B in morning, drug B in the afternoon, and drug A inthe evening). Patients, on the other hand, are not typically able tocomply with such complicated dosing schedules. As a result, their doctormay give them one bottle having combination drugs A and B, and ask thepatient to take that combination two or three times per day when it maynot be necessary, for example, for some dosings of one drug in theevening. In addition, the side effects of drug components may beadditive, and drug interactions are often compounded with combinationsof therapy. The pumps of the drug-delivery device 90 may, however,achieve the same clinical effect without comprising one drugs efficacyand desired timing.

FIG. 6 illustrates yet another embodiment of a drug-delivery device 200.The device 200 includes a reservoir 300, which is configured to containa liquid comprising a therapeutic agent (e.g., a drug), and a cannula310 that is in fluid communication with the reservoir 300. The cannula310 may be manufactured from parylene or other suitable material. At ornear its distal end 317, the cannula 310 includes an outlet 315 that isconfigured to be in fluid communication with a patient (e.g., apatient's eye). The device 200 also includes a first electrode 320, asecond electrode 330, and a material 340 that is in electricalcommunication with the first and second electrodes 320, 330. At leastone of the electrodes 320, 330 is planar. To ensure that the material340 is in electrical communication with both electrodes 320, 330, theelectrodes may be interdigitated with one another. In one embodiment, avoltage applied between the first electrode 320 and the second electrode330 produces gas from the material 340. The produced gas forces theliquid to flow from the reservoir 300, through the cannula 310, to theoutlet 315. In other words, the first and second electrodes 320, 330operate an electrolytic pump that drives liquid from the reservoir 300,through the cannula 310, to the outlet 315.

In greater detail, electrolytic pumps use electrochemically-generatedgases to generate pressure that dispenses fluid (e.g., a drug-containingliquid) from one location to another. For example, application of asuitable voltage across two electrodes (typically gold, palladium, orplatinum) immersed in an aqueous electrolyte produces oxygen andhydrogen gases that can be used to apply pressure to a piston, membrane,or other transducer. Electrolysis of water occurs rapidly and reversiblyin the presence of a catalyst such as platinum, which in the absence ofan applied voltage catalyzes recombination of the hydrogen and oxygen toreform water. As described, in certain embodiments, the drug-deliverydevice 200 uses electrolytically-generated gas to pump the drug from thereservoir 300 through the cannula 310 to the patient. A check valve (notshown) at the distal end 317 of the cannula 310 may be employed toprevent forward flow of drug until enough pressure is generated by thepumping apparatus. Such electrolytic pumping can facilitate theelectronic control of drug delivery.

Electrolytic pumps offer several advantages for drug delivery. Theirlow-temperature, low-voltage, and low-power operation suits them wellfor long-term operation in vivo. For ocular applications, electrolyticpumps produce negligible heat and can also achieve high stress-strainrelationships. Moreover, they lend themselves readily to the use ofmicroelectronics to control the voltage applied to the pump (andtherefore the temporal pattern of pressure generation), which allowsoperation the device 200 in either bolus and/or continuous dosage mode.Radio-frequency (RF) transmission and reception may also be used toprovide wireless power and control of the microelectronic circuitry thatoperates the pump.

Electrolysis in a chamber in fluid communication with its exteriorgenerates gases that force working fluid out of the chamber. Reversingthe polarity of the applied voltage can reverse the process, therebyrestoring the chamber to its original state. Since a small tricklecharge can prevent this reverse process, the drug-delivery device 200can be held in place with little power (i.e., the device 200 islatchable).

With reference still to FIG. 6, the drug-delivery device 200 may beconstructed of a first portion 250 and a second portion 260 mountedthereon. As illustrated, the first portion 250 may include the cannula310, the first electrode 320, and the second electrode 330. By mountingthe second portion 260 onto the first portion 250, the reservoir 300 isformed therebetween. In certain embodiments, the second portion 260includes a liquid- and gas-impermeable material (e.g., silicone) that isself-sealing to repeated punctures, as described above.

FIGS. 7A and 7B schematically illustrate a top-cross-sectional view anda side-cross-sectional view, respectively, of the first portion 250 ofthe drug-delivery device 200 in accordance with another embodiment ofthe invention. As illustrated, the first portion 250 includes a supportlayer 305, the first electrode 320, and the second electrode 330. Thefirst and second electrodes 320, 330 are positioned over the supportlayer 305, and at least one of the first electrode 320 and the secondelectrode 330 is planar.

In certain embodiments, the support layer 305 is liquid- andgas-impermeable and is also electrically insulative such that, absentany conductive material above the support layer 305, the first electrode320 and the second electrode 330 are electrically insulated from oneanother. The first electrode 320 and the second electrode 330 areconfigured to be in electrical communication with a voltage source (notshown) that applies a voltage difference across the first electrode 320and the second electrode 330.

As illustrated in FIGS. 7A and 7B, in certain embodiments, the first andsecond electrodes 320, 330 are co-planar with one another. In certainembodiments, at least one of the first and second electrodes 320, 330 ispatterned to have elongations or fingers within the plane defined by theelectrode. For example, as illustrated in FIG. 7A, the first electrode320 may be elongate and extend along a generally circular perimeter withradial elongations 322 that extend towards the center of the circularperimeter. For its part, the second electrode 330 may have a centerelongate portion 332 with generally perpendicular elongations 334 thatextend therefrom. In certain embodiments, the elongations 334 define agenerally circular perimeter within the generally circular perimeter ofthe first electrode 320, as illustrated in FIG. 7A. Other shapes andconfigurations of the first electrode 320 and the second electrode 330are also compatible with embodiments of the drug-delivery device 200described herein.

In certain embodiments, the first portion 250 also includes an outerwall 360 that is liquid- and gas-impermeable. As described more fullybelow, the outer wall 360 is configured to be bonded to a correspondingwall of the second portion 260 of the device 200.

The first portion 250 of the drug-delivery device 200 may also include afirst structure 370 between the first electrode 320 and the secondelectrode 330. As illustrated in FIGS. 7A and 7B, the first structure370 may be a generally circular wall extending generally perpendicularlyfrom the support layer 305. In certain embodiments, the first structure370 includes one or more fluid passageways 372 through which a liquidcan flow between a first region 380 above the first electrode 320 and asecond region 385 above the second electrode 330, as described morefully below. The first structure 370 may also include a liquid-permeablebut gas-impermeable barrier between the first and second regions 380,385.

In certain embodiments, the first portion 250 also includes a secondstructure 374 above the first electrode 320 and a third structure 376above the second electrode 330. The second structure 374 may bemechanically coupled to the first structure 370 and the outer wall 360,as illustrated in FIG. 7B, such that the support layer 305, the outerwall 360, the first structure 370, and the second structure 374 definethe first region 380 containing the first electrode 320. In addition,the third structure 376 may be mechanically coupled to the firststructure 370, as illustrated in FIG. 7B, such that the support layer305, the first structure 370, and the third structure 376 define thesecond region 385 containing the second electrode 330.

The second structure 374 and/or the third structure 376 may be flexibleand liquid- and gas-impermeable. For example, the second structure 374and/or the third structure 376 may include a flexible membrane (e.g.,corrugated parylene film). The second structure 374 and/or the thirdstructure 376 may be configured to expand and contract with increasesand decreases in pressure in the corresponding first region 380 and/orsecond region 385. In some such embodiments, both the second and thirdstructures 372, 374 include or represent portions of the same flexiblemembrane, as illustrated in FIG. 7B.

FIGS. 8A and 8B schematically illustrate a top view and aside-cross-sectional view, respectively, of an embodiment of thedrug-delivery device 200 including the first and second portions 250,260. The second portion 260 includes a liquid-impermeable wall that isconfigured to be bonded to the first portion 250 of the device 200. Asillustrated in FIGS. 8A and 8B, the second portion 260 may be bonded tothe outer wall 360 of the first portion 250 such that the second portion260, the second structure 374, and the third structure 376 define thereservoir 300 configured to contain a drug.

In certain embodiments, the first region 380 and the second region 385contain a material 340 that emits gas when a sufficient voltage isapplied to the material 340. For example, in certain embodiments, thematerial 340 includes water that is electrolytically separated by anapplied voltage into hydrogen gas and oxygen gas. As illustrated in FIG.8B, both the second and third structures 374, 376 may include liquid-and gas-impermeable flexible membranes. Gas generated at the firstelectrode 320 increases the pressure in the first region 380, therebyflexing the second structure 374 towards the reservoir 300. Furthermore,gas generated at the second electrode 330 increases the pressure in thesecond region 385, thereby flexing the third structure 376 towards thereservoir 300. The flexing of the second structure 374 and/or the thirdstructure 376 forces liquid (e.g., containing a therapeutic agent, suchas a drug) to flow from the reservoir 300, through the cannula 310, tothe one or more outlets 315.

In one embodiment, the device 200 restricts gas produced at the firstelectrode 320 from mixing with gas produced at the second electrode 330.For example, as illustrated in FIG. 8B, when the material 340 compriseswater, hydrogen gas produced at the first electrode 320 is generallyrestricted to the first region 380 and the hydrogen gas produced at theother, second electrode 330 is generally restricted to the second region385.

FIGS. 9A-9D schematically illustrate various views of the drug-deliverydevice 200 of FIGS. 8A and 8B. FIG. 9A schematically illustrates a topview of the device 200 with the first electrode 320, the secondelectrode 330, the second portion 260, and the cannula 310. FIG. 9Bschematically illustrates a top partially cut-away view that shows thefirst electrode 320, the second electrode 330, the second portion 260,the cannula 310, the second structure 374, and the third structure 376.As shown in FIG. 9B, the second structure 374 and the third structure376 are portions of a membrane extending across the first portion 250 ofthe device 200. FIG. 9C shows a portion of the first region 380, thefirst electrode 320 in the first region 380, the second region 385, thesecond electrode 330 within the second region 385, the second structure374, the third structure 376, the second portion 260, and the cannula310. The device 200 shown in FIG. 9D does not contain either thematerial 340 or the drug, but otherwise corresponds to the filled device200 shown in FIG. 8B.

FIG. 10 schematically illustrates various views of the drug-deliverydevice 200 that includes an injection port 410 configured to receive aninjection needle 420. In one embodiment, the injection port 410 is partof the first portion 250 of the device 200, while in another embodimentthe injection port 410 is part of the second portion 260 of the device200. The injection port 410 is in fluid communication with the reservoir300 of the device 200 to facilitate refilling of the device 200 whilethe device 200 is implanted. In addition, as illustrated in FIG. 10, thedevice 200 may include suture tabs 400 for fastening the device 200 to apatient's body (e.g., to the surface of the patient's eye).

FIG. 11 schematically illustrates the internal structure of an exemplaryinjection port 410. Injection needle 420 pierces a surface 500 of theinjection port 410 through needle injection guide 510, and thereby gainsaccess to injection vestibule 520. Injection of fluid from the needle420 into the vestibule 520 forces liquid through the injection portvalve 530 and into the reservoir 540.

In certain embodiments, the device 200 is powered by an internal battery(not shown), while in other embodiments, the device 200 is powered by anexternal source (not shown). Alternatively, both a battery and anexternal source may be used. For example, even though the power can berecharged wirelessly, a smaller battery may be used to store the powerfor a week, thereby advantageously keeping the device small andminimally invasive.

The external source can be electrically coupled to the device 200 usingwires or by wireless means (e.g., by using RF transmitters andreceivers). By utilizing an external source and avoiding the use of aninternal battery, the device 200 can advantageously be made evensmaller, and therefore less invasive. In addition, by wirelesslycontrolling the operation of the device 200 (e.g., turning it on andoff), a handheld transmitter can be programmed to send a signal thatcommunicates with the device to power the device when needed. Forexample, at times when less drug is needed, less power is transmitted,and less drug is pumped. There may also be some threshold cutoff on theexternal power applicator that limits the implant from pumping too muchdrug. Wireless power may be inductively imparted through the use ofcoils built into the implant and the external transmitter.

In another embodiment, the device 200 includes an integrated circuit forcontrolling operation of the device 200. Examples of integrated circuitscompatible with embodiments of the drug-delivery devices describedherein include, but are not limited to, single-chip application specificintegrated circuits (ASICs) and application specific standard products(ASSPs) that have become more common for implantable medicalapplications. In some embodiments, such integrated circuits consume aslittle power as possible to, for example, extend battery life andtherefore lengthen the time between invasive replacement procedures. Inaddition, the device 200 may include microelectronics to control thedosage and release, sensors for feedback control, anchoring structuresto hold the device in place, supports to keep the reservoir fromcollapsing on itself when emptied, filtering structures, additionalvalves for more accurate flow control, a flow regulator to remove theadverse effects of pressure on drug delivery, and a programmabletelemetry interface.

In one embodiment, as illustrated in FIGS. 1A and 1B, the drug-deliverydevice 5 includes three individual structural layers 10, 20, 50. One,two, or all three of the layers 10, 20, 50 may be made of abiocompatible polymer, such as PDMS or parylene. In one embodiment, atleast one of the structural layers 10, 20, 50 is formed using alithographic process (e.g., soft lithography). FIGS. 12A-12Kschematically illustrate an exemplary lithographic process. Asillustrated in FIG. 12A, a substrate (e.g., a silicon wafer) isprovided. A photoresist layer may then be formed on the substrate (e.g.,by spin-coating a light-sensitive liquid onto the substrate), as shownin FIG. 12B. Suitable photoresists are well-known to those skilled inthe art and include, but are not limited to, diazonaphthoquinone, phenolformaldehyde resin, and various epoxy-based polymers, such as thepolymer known as SU-8. As illustrated in FIG. 12C, the photoresist layermay then be patterned to cover a first portion of the substrate and tonot cover a second portion of the substrate. For example, ultravioletlight may be shone through a mask onto the photoresist-coated wafer,thereby transferring the mask pattern to the photoresist layer.Treatment of the wafer by well-known photoresist development techniquescan then be used to remove the portions of the photoresist layer thatwere exposed to the ultraviolet light. Persons skilled in the art oflithographic techniques are able to select appropriate materials andprocess steps for forming the patterned photoresist layer in accordancewith the embodiments described herein.

As illustrated in FIG. 12D, the portion of the substrate that is notcovered by the patterned photoresist layer may be etched (e.g., by deepreactive-ion etching), thereby leaving untouched the portions of thesilicon wafer protected by the photoresist layer. As illustrated in FIG.12E, the patterned photoresist layer may then be removed. For example,after washing with a solvent, such as acetone, the photoresist layer isremoved and the entire wafer can be cleaned through use of oxygen plasmato remove any remaining photoresist. As illustrated in FIG. 12F, a moldrelease layer (e.g., parylene, a widely-used polymer of p-xylene) may beformed on the substrate to facilitate removal of the PDMS layer from thesilicon wafer. Other materials can be used as the mold release layer inother embodiments. As illustrated in FIG. 12G, a structural layer (e.g.,PDMS silicone) may be formed on the mold release layer. For example,PDMS can be poured over the silicon wafer and allowed to cure either bystanding at room temperature or accelerated by heating (e.g., to 75° C.for 45 minutes). As illustrated in FIG. 12H, the structural layer maythen be removed from the substrate, thereby providing the structurallayer illustrated in FIG. 12I. In certain embodiments, the molded PDMSlayer contains multiple copies of the structural layer, and each copy ofthe structural layer is separated from the others. Excess material canbe removed from the structural layer, as illustrated in FIG. 12J,thereby providing the structural layer illustrated in FIG. 12K, which isready for assembly with the other structural layers.

The individual structural layers can be assembled and bonded together incertain embodiments by treating the surface of one or more of thestructural layers with oxygen plasma for about one minute, although thetime is not critical. Oxygen plasma changes the surface of the PDMS fromhydrophobic to hydrophilic.

In certain embodiments, with reference again to FIG. 1A, the bottomlayer 50 and the middle layer 20 are placed into a plasma chamber withthe sides that are to be bonded facing the plasma. Once the surfaceshave been treated, the two pieces 20, 50 may be aligned with the aid ofa polar liquid (e.g., ethanol, water, etc.). The liquid preserves thereactive hydrophilic surface providing more time to align the twolayers. It also makes the two pieces 20, 50 easier to manipulate foralignment since it lubricates the surfaces, which are otherwise sticky.The two-layer assembly can then be placed back into the chamber alongwith the top layer 10 and the treatment and alignment procedurerepeated. The entire assembly can then be baked (e.g., at 100° C. for 45minutes) to reinforce the bonds. In practice, the bonded siliconeappeared homogeneous by scanning electron microscopy and opticalobservation. Tests with pressurized N₂ showed that the bonded siliconeassembly withstood pressures of at least 25 psi.

With reference to FIGS. 1A and 1B, in certain embodiments, the orifice40 is made by inserting a small diameter coring needle into a sheet ofsilicone rubber that later forms the upper surface of the cannula 110.Other methods can also be used to generate this feature. The coringneedle removes material to create the orifice 40. The valve seat 80 maybe a post that protrudes from the bottom of the cannula 110 and extendsthe height of the channel 72 to meet the top of the cannula 110. Duringassembly, the orifice 40 is centered over the valve seat 80 and rests onit to form the valve 120. In this configuration, the valve 120 is saidto be “normally-closed” and fluid will not pass through. Fluid pressurein the cannula 110 exceeding a certain value (i.e., a cracking pressure)opens the valve 120 and allows fluid to exit the drug-delivery device 5through a gap between valve seat 80 and the movable element 122, asillustrated in FIG. 4A.

FIGS. 13A-13M schematically illustrate one exemplary process for forminga drug-delivery device that includes electrolytic pumping, such as thedrug-delivery device 200 depicted in FIG. 6, although other processesmay also be employed in forming the drug-delivery device.

As illustrated in FIG. 13A, a bare silicon substrate may be providedand, as illustrated in FIG. 13B, a dielectric layer (e.g., a thermalsilicon dioxide layer about 4000 Å thick) may be grown on the siliconsubstrate. This silicon oxide layer electrically insulates the substrateand electrolysis electrodes.

As illustrated in FIG. 13C, electrolysis electrodes (e.g., made ofTi/Pt, 200 Å and 2000 Å thick, respectively) may be then formed over thedielectric layer (e.g., deposited and lithographically patterned). Thedielectric layer may be patterned and etched briefly with XeF₂ to removea portion of the dielectric layer, thereby exposing a portion of thesubstrate. This process can also roughen the exposed silicon surface, asillustrated in FIG. 13D. A first sacrificial photoresist layer (e.g., 5μm thick) can be spun and patterned on the substrate, as illustrated inFIG. 13E. The first sacrificial photoresist layer facilitates therelease of the cannula from the supporting silicon substrate at the endof the fabrication process. A first structural layer (e.g., a 7.5 μmthick parylene layer) can then be deposited and patterned on the firstsacrificial layer, as illustrated in FIG. 13F. The first structurallayer will become the bottom wall of the drug-delivery cannula. Asillustrated in FIG. 13G, a second sacrificial layer (e.g., a 25 μm thickphotoresist layer, spun and patterned) can be formed over the firststructural layer. As illustrated in FIG. 13H, a second structural layer(e.g., a 7.5 μm thick parylene layer) can then be deposited on thesecond sacrificial layer. The second structural layer will become thetop and side walls of the cannula. The first and second structurallayers can then be patterned, as illustrated in FIGS. 13I and 13J. Forexample, a Cr/Au etch mask layer for removing unwanted parylene (200 Åand 2000 Å thick, respectively) can be deposited and patterned on thesubstrate, as illustrated in FIG. 13I. The parylene can be patterned inan oxygen plasma through use of the Cr/Au masking layer, asschematically illustrated in FIG. 13J. A third structural layer (e.g.,an SU-8 photoresist layer 70 μm thick) can be spun and patterned on thesubstrate, as illustrated in FIG. 13K. The SU-8 layer can support thecannula and prevent its collapse when a drug reservoir is attached tothe base layer. The sacrificial photoresist layers are then removed bydissolving them in acetone, as illustrated in FIG. 13L. The cannula canthen be peeled up from the surface of the roughened silicon substrateand broken off the silicon substrate directly beneath the cannula toform a free-standing cannula, as illustrated in FIG. 13M.

In one embodiment, the drug-delivery device 5, 90, 200 is implanted byattaching the main body of the device 5, 90, 200 to the top of apatient's eye and inserting the cannula 110, 310 into the anterior orthe posterior segment of the eye. The device 5, 90, 200 may be affixedto the eye through use of current ophthalmic techniques such as suturesor eye tacks. In one embodiment, a method of using the device 200includes applying a first voltage between the first and secondelectrodes 320, 330 to produce gas from the material 340 in electricalcommunication with the electrodes. The gas forces liquid to flow fromthe reservoir 300, through the cannula 310, to the outlet 315 of thedevice 200. In certain embodiments, the method also includes applying asecond voltage between the first electrode 320 and the second electrode330 to produce the material 340 from the gas. In this way, the device200 is used in a reversible manner in which the material 340 isregenerated from the gases, thereby avoiding having to refill the device200 with the material 340. In certain embodiments, the material 340comprises water and the gas comprises hydrogen gas and oxygen gas. Incertain embodiments, the first voltage and the second voltage areopposite in sign.

EXAMPLE

A device having a flexible parylene transscleral cannula allowing fortargeted delivery to tissues in both the anterior and posterior segmentsof a patient's eye is described below. This electrochemically drivendrug-delivery device was demonstrated to provide flow rates suitable forocular drug therapy (i.e., pL/min to μL/min) Both continuous and bolusdrug-delivery modes were performed to achieve accurate delivery of atarget volume of 250 nL. An encapsulation packaging technique wasdeveloped for acute surgical studies and preliminary ex vivodrug-delivery experiments in porcine eyes were performed.

The electrolysis of water results in the phase transformation of liquidto gas and provides the actuation used to drive drug delivery in thisexample device. The net result of the electrolysis is the production ofoxygen and hydrogen gas that contributes to a volume expansion of abouta thousand times greater than that of the water used in the reaction.This gas evolution process proceeds even in a pressurized environment(e.g., 200 MPa).

To drive gas generation and thus pumping, current control is useful dueto its direct correlation to pump rate and volume. If current is used todrive the reaction, the theoretical pump rate (q_(theoretical) in m³/s)at atmospheric pressure is given by:

q _(theoretical)=0.75(I/F)V _(m),

where I is current in amperes, F is Faraday's constant, and V_(m) is themolar gas volume at 25° C. and atmospheric pressure. The theoreticalgenerated or dosed gas volume (V_(theoretical) in m³) can be determinedby:V _(theoretical) =q _(theoretical) t,where t is the duration (in sec) that the current is applied. Theefficiency (η) of an electrolysis actuator as a pump can be defined as:η=V _(experimental) /V _(theoretical),where V_(experimental) is the actual volume of the generated hydrogenand oxygen gases. Efficiency in electrochemical systems is affected by anumber of parameters including electrode parameters (e.g., material,surface area, geometry, and surface conditions), mass transferparameters (e.g., transport mode, surface concentration, andadsorption), external parameters (e.g., temperature, pressure, andtime), solution parameters (e.g., bulk concentration of electroactivespecies, concentration of other species and solvent), and electricalparameters (e.g., potential, current, and quantity of electricity).

The electrolysis pump included two interdigitated platinum electrodesimmersed in an electrolyte. This electrode geometry improves pumpingefficiency by reducing the current path through the solution, whichserves to lower the heat generation. The gasses generated resulted in aninternal pressure increase in the sealed reservoir, which caused drug tobe delivered through the cannula and into the patient's eye.Electrolysis is a reversible process and ceases when the applied signalis turned off, thereby allowing the gradual recombination of hydrogenand oxygen to water.

Pumped drug entered the flexible transscleral cannula through a smallport connected to the pump, while the generated gases remained trappedinside the reservoir. Parylene was selected as the cannula material forits mechanical strength, biocompatibility, and ease of integration. Itis a USP Class VI material suitable for the construction of implants andis well-established as a MEMS material. The pump/cannula portion wasfabricated using silicon micromachining and the reservoir portion by thecasting of silicone rubber against a master mold.

More specifically, the fabrication process of the pump and cannula chipstarted with a thermally oxidized silicon substrate (5000 Å). LOR 3B(MicroChem Corporation, Newton, Mass.) was spun on at 3 krpm followed byAZ 1518 (AZ Electronic Materials, Branchburg, N.J.) at 3 krpm. Ti—Pt(200/2000 Å) was e-beam evaporated and patterned by lift-off in a ST-22photoresist stripper (ATMI, Danbury, Conn.) to define the interdigitatedelectrodes. A second lithography step was performed (AZ 1518 at 3 krpm)to define the cannula footprint. The oxide layer was etched usingbuffered HF acid to expose the Si below. The photoresist was strippedand then the exposed Si was roughened by two cycles of XeF₂ etching. Thefirst sacrificial photoresist layer (AZ 4620 spun at 2.75 krpm and hardbaked to yield a 5 micron thick layer) was applied to facilitate releaseof the cannula from the substrate. The first parylene C layer (7.5microns) forming the bottom of the cannula was deposited followed bythermal evaporation of a 2000 Å thick Cr etch mask. Followinglithography (AZ 4620 at 500 rpm), the Cr was etched in Cr-7 (Cyanteck,Fremont, Calif.) and the photoresist stripped. The parylene layer wasthen patterned in an oxygen plasma and the Cr etch mask was removedusing Cr-7. A second photoresist sacrificial layer was deposited (AZ4620 spun at 450 rpm and hard baked to yield a 25 micron thick layer) todefine the channel height. A second parylene layer of 7.5 microns wasdeposited to complete the cannula. To define the cannula from theparylene/photoresist/parylene sandwich, Ti/Au (200/2000 Å) was depositedas an etch mask. The etch mask was patterned (AZ 4620 spun at 425 rpm)and etched first with Au etchant TFA (Transene Company, Inc., Danvers,Mass.) and then 10% HF. Finally, the sandwich was etched in oxygenplasma and the masking layer was stripped (Au etching TFA and 10% HF).Following the etch, the entire wafer was cleaned in 5% HF dip and byexposure to oxygen plasma. SU-8 2200 (MicroChem Corporation, Newton,Mass.) was spun at 2200 rpm resulting in a 70 micron thick layer afterpost baking. The sacrificial photoresist was removed by dissolving in a40° C. acetone solution for one day. The individual cannulae werereleased manually by gently lifting them off the substrate. Finally,individual dies were separated and the remaining silicon beneath eachcannula was removed by scribing and breaking it off.

The pump chip containing the electrolysis actuator and cannula wascombined with the drug reservoir and electrical wiring. Electrical wireswere bonded to the electrode contact pads using OHMEX-AG conductiveepoxy (Transene Company, Inc., Danvers, Mass.). The epoxy was cured at150° C. for 15 hours under vacuum. The pump chip and reservoir were thenassembled using an encapsulation technique based on silicone softlithography as described above.

To shape the package to fit comfortably on the curved contour of theeyeball, a silicone spacer (SYLGARD 184, Dow Corning, Midland, Mich.)was casted against a stainless steel sphere of 17.5 mm in diameter. Thislayer of partially cured silicone (10:1 base to curing agent ratio) wascured at 65° C. for 20 minutes. The sphere was removed and the resultingcrater was filled with wax. A silicone reservoir was prepared by castingagainst a conventionally machined acrylic mold, partially cured at 65°C. for 20 minutes. The mold produced a reservoir with internaldimensions of 6 mm×6 mm×1.5 mm. The silicone reservoir was aligned tothe chip and spacer and the parylene cannula was then immersed in DIwater, which serves as a mask to prevent coating by silicone rubberduring the encapsulation step, thereby exploiting the hydrophobicity ofsilicone rubber. The stack was immersed in silicone prepolymer and curedat room temperature for 24 hours. Extraneous silicone material wasremoved from the device to complete the assembly process.

To investigate the performance of the electrolysis pump, experimentsexamining continuous delivery, bolus delivery, pump efficiency, gasrecombination, and backpressure were conducted. For these tests, acustom testing apparatus was laser-machined (Mini/Helix 8000, Epilog,Golden, Colo.) in acrylic. The experimental setup included acomputer-controlled CCD camera (PL-A662, PixeLINK, Ottawa, Ontario,Canada) for collecting flow data from a calibrated micro-pipette(Accu-Fill 90, Becton, Dickinson and Company) attached to the outputport of the test fixture. Testing was performed using deionized water asthe electrolyte. The electrolysis was initiated under constant currentconditions (50 μA to 1.25 mA) for continuous delivery operation. Therelationship between efficiency and recombination of hydrogen and oxygento water was studied.

Bolus delivery was also examined A constant current pulse (0.5, 1.0, and1.5 mA) was applied for 1, 2, and 3 seconds. Repeated trials wereperformed (n=4) to obtain average dosing volume. Normal IOP ranges from5-22 mmHg (15.5±2.6 mmHg (mean±SD)). Values outside this rangecorrespond to abnormal IOP, which is a characteristic of glaucoma (>22mmHg). Thus, it is helpful to characterize pump performance under thesephysiologically relevant conditions. The experimental setup was modifiedto include a water column attached to the outlet of the micro-pipette.Backpressure was applied to the drug-delivery device by adjusting theheight of the water column. Data was collected for backpressurescorresponding to normal IOP (20 mmHg) and abnormal IOP (0 and 70 mmHg).

The prototype drug-delivery devices were implanted in enucleated porcineeyes. Preliminary ex vivo surgical modeling in enucleated porcine eyesis useful to prepare for device demonstration in vivo. The operation ofeach surgical device was tested prior to the surgical experiment tocheck for clogs and integrity of the electrical connections. The drugreservoir was filled with dyed deionized water and then the reservoirswere manually depressed, which generates sufficient pressure to expelthe fluid from the reservoir. A second test was conducted to verifyoperation of the electrolysis pump by connecting to an external powersupply and driving fluid from the reservoir by electrolysis pumping. Anenucleated porcine eye was prepared for the surgical study and a limbalincision was made (between the cornea and sclera). The cannula wasimplanted through the incision into the anterior chamber. The enucleatedporcine eye was pressurized at 15 mmHg by using an infusion line.Constant current (0.5 mA) was applied for 1 minute. The device wassurgically removed after the experiment.

The electrolysis pump was operated at flow rates in the pL/min to μL/minrange using driving currents from 5 μA to 1.25 mA (FIGS. 14A and 14B).The highest rate was 7 μL/min for 1.25 mA and the lowest was 438 pL/minat 5 μA. Both data sets are corrected to compensate for the evaporationof fluid during testing. Flow rates below about 2 μL/min are preferredfor ocular drug delivery. This is consistent with naturally occurringflow rates in the eye; the ciliary body of the eye produces aqueoushumor at 2.4±0.6 μL/min in adults. As current decreases, it was observedthat pumping efficiency, which ranged from 24-49%, also decreased (FIG.14C). Electrolysis-driven pumping efficiency is affected by thecompetitive recombination of hydrogen and oxygen gases to water. Thiseffect is further enhanced by exposure to the platinum electrolysiselectrodes that serve to catalyze the recombination reaction. In FIG.14D, a typical accumulated volume curve is shown that illustrates theeffect of recombination after the applied current is turned off. Themeasured recombination rate was 62 mL/min.

Bolus delivery mode was also evaluated (FIG. 15). If the desired dosingregimen is 250 nL per dose, this volume can be obtained by driving thepump for a short duration that is determined by the magnitude of theapplied current. For example, a 1.0 mA driving current will dose 250 nLin 2.36 seconds. For 1.5 mA current, the pulse time can be set as 1.75seconds. Under normal operation in the eye, the drug-delivery devicewill experience a backpressure equivalent to the IOP of the eye.Benchtop experiments indicated that the pump was able to supplysufficient drug flow over the range of normal and abnormal IOPequivalent backpressures (FIG. 16). The flow rates varied 30% comparedto normal IOP over the tested backpressure range.

Initial surgical results showed promising results in enucleated porcineeyes. Following removal of the device after the surgical experiment,post surgical examination of the cornea revealed a small blue spot abovethe iris near the position of the cannula tip indicating that dye wasdelivered into the eye.

Additional details on some of the drug-delivery devices described hereinmay be found in U.S. patent application Ser. No. 11/686,310 entitled“MEMS Device and Method for Delivery of Therapeutic Agents,” thedisclosure of which is hereby incorporated herein by reference in itsentirety.

Having described certain embodiments of the invention, it will beapparent to those of ordinary skill in the art that other embodimentsincorporating the concepts disclosed herein may be used withoutdeparting from the spirit and scope of the invention. Accordingly, thedescribed embodiments are to be considered in all respects as onlyillustrative and not restrictive.

What is claimed is:
 1. A drug-delivery device, comprising: a refillablereservoir having a self-resealing upper layer that is pierceable by aneedle for refilling and an opposed lower layer that is unpuncturable bythe needle so as to protect an eye from injury, and containing a liquidthat comprises a therapeutic agent selected from the group consisting ofacetazolamide, betaxolol, bevacizumab, bimatoprost, brimonidine,brinzolamide, carbidopa, carteolol, cidofovir, cyclosporine,dorzolamide, epinephrine, a growth factor, irinotecan, ketorolactromethamine, ketotifen fumarate, latanoprost, levobetaxolol,levobunolol, levodopa, levofloxacin, loratadine, loteprednol etabonate,metipranolol, naphazoline, ofloxacin, pegaptanib, pemirolast,pheniramine maleate, pilocarpine, pseudoephedrine, ranibizumab, asteroid, timolol, travoprost, trifluridine, tumor necrosis factorblocker, unoprostone isopropyl, valganciclovir, verteporfin, vitravene,a drug that prevents beta amyloid deposition in the retina, a drug thatprevents beta amyloid deposition in the brain, an anti-human complementactivation blocker that blocks complement H activation in the eye, andsiRNA molecules; a cannula in fluid communication with the reservoir,the cannula having an outlet for delivering the therapeutic agent to apatient; a memory for storing a drug-delivery regimen; a microprocessorfor executing the stored drug-delivery regimen; and a sensor fordetecting a position and an activity of the patient, the microprocessordetermining at least one of a frequency, time, or dosage of the liquiddelivered to the patient based thereon and responsively controllingdelivery of the liquid.
 2. The device of claim 1, wherein the device isshaped to conform to a curved contour of the eye.
 3. The device of claim1, wherein the lower layer is implanted adjacent to the sclera of theeye and the cannula is inserted into the eye through the sclera tofacilitate delivery of drug from the reservoir into the eye.
 4. Thedevice of claim 1, further comprising a sensor for receiving feedbackfrom the patient, the microprocessor being configured to modify thedrug-delivery regimen based on the feedback.
 5. The device of claim 1,further comprising a sensor for detecting a measured eye pressure forthe patient.
 6. The device of claim 5, wherein the sensor monitorsphysiological effects of the therapeutic agent present for determining aresidual amount of the therapeutic agent in a tissue of the patient. 7.The device of claim 1, further comprising a transceiver for receivingwireless instructions that reprogram the drug-delivery regimen.
 8. Thedevice of claim 1, further comprising: an electrolysis chamber includinga gas-impermeable flexible membrane configured to expand and contractwith increases and decreases in pressure in the electrolysis chamber,the flexible membrane also constituting a portion of the reservoir; andat least two electrodes in the electrolysis chamber, the electrodesbeing responsive to the microprocessor to produce gas in theelectrolysis chamber to expand the membrane and thereby force liquidfrom the reservoir through the cannula.
 9. The device of claim 1,further comprising a valve disposed in the cannula, wherein the valvecontrols fluid delivery, maintains a constant flow rate independent ofvariations in pressure driving a fluid flow through the cannula, andprevents backflow.